Search

Your search keyword '"Chenevix-Trench, G"' showing total 921 results
Start Over Author "Chenevix-Trench, G"

Refine your results

921 results on '"Chenevix-Trench, G"'

203. Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

Author

Bernstein, J.L., Teraoka, S., Southey, M.C., Jenkins, M.A., Andrulis, I.L., Knight, J.A., John, E.M., Lapinski, R., Wolitzer, A.L., Whittemore, A.S., West, D., Seminara, D., Olson, E.R., Spurdle, A.B., Chenevix-Trench, G., Giles, G.G., Hopper, J.L., and Concannon, P.

Abstract

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population. Hum Mutat 27(11), 1122-1128, 2006. Published 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2006
Full Text
View/download PDF

204. Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals.

Author

Jekimovs, C R, Chen, X, Arnold, J, Gatei, M, Richard, D J, Spurdle, A B, Khanna, K K, and Chenevix-Trench, G

Subjects
BREAST cancer, CELL culture, MESSENGER RNA, CELL lines, RNA, CARCINOGENS
Abstract

A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95%of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20%of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.British Journal of Cancer (2005) 92, 784-790. doi:10.1038/sj.bjc.6602381 www.bjcancer.com Published online 8 February 2005 [ABSTRACT FROM AUTHOR]

Published
2005
Full Text
View/download PDF

205. Classification of BRCA 1 missense variants of unknown clinical significance.

Author

Phelan, C. M., Ðapić, V., Tice, B., Favis, R., Kwan, E., Barany, F., Manoukian, S., Radice, P., van der Luijt, R. B., van Nesselrooij, B. P. M., Chenevix-Trench, G., Caldes, T., de La Hoya, M., Lindquist, S., Tavilgian, S. V., Goldgar, D., Borg, Å., Narod, S. A., and Monteiro, A. N. A.

Subjects
TUMOR suppressor genes, CANCER genetics, GENETIC mutation, CANCER, CANCER in women, GENETIC transcription
Abstract

Background: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCAI are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. Objective: To investigate a panel of missense variants. Methods and results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396–1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S15121, M1628T, M1628V, T16851, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R were specifically investigated. Contusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability. [ABSTRACT FROM AUTHOR]

Published
2005
Full Text
View/download PDF

209. CYP17 promoter polymorphism and breast cancer in Australian women under age forty years.

Author

Spurdle, Amanda B., Hopper, John L., Spurdle, A B, Hopper, J L, Dite, G S, Chen, X, Cui, J, McCredie, M R, Giles, G G, Southey, M C, Venter, D J, Easton, D F, and Chenevix-Trench, G

Subjects
CANCER genetics, CANCER in women, PROMOTERS (Genetics), DNA analysis, AGE distribution, AGE factors in disease, ALLELES, BREAST tumors, COMPARATIVE studies, DNA probes, GENES, GENETIC polymorphisms, RESEARCH methodology, MEDICAL cooperation, GENETIC mutation, ONCOGENES, OXIDOREDUCTASES, POLYMERASE chain reaction, RESEARCH, LOGISTIC regression analysis, EVALUATION research, BRCA genes, RELATIVE medical risk, CASE-control method, GENOTYPES
Abstract

Background: The cytochrome P450c17alpha enzyme functions in the steroid biosynthesis pathway, and altered endogenous steroid hormone levels have been reported to be associated with a T to C polymorphism in the 5' promoter region of the CYP17 gene. Because steroid hormone exposure is known to influence breast cancer risk, we conducted a population-based, case-control-family study to assess the relationship between the CYP17 promoter polymorphism and early-onset breast cancer.Methods: Case subjects under 40 years of age at diagnosis of a first primary breast cancer, population-sampled control subjects, and the relatives of both case and control subjects were interviewed to record family history of breast cancer and other risk factors. CYP17 genotype was determined in 369 case subjects, 284 control subjects, and 91 relatives of case subjects. Genotype distributions were compared by logistic regression, and cumulative risk was estimated by a modified segregation analysis. All statistical tests were two-tailed.Results: Compared with the TT genotype (i.e., individuals homozygous for the T allele), the TC genotype was not associated with increased breast cancer risk (P: =.7). Compared with the TT and TC genotypes combined, the CC genotype was associated with a relative risk of 1. 81 (95% confidence interval [CI] = 1.15-2.86; P: =.01) before adjustment for measured risk factors and 1.63 (95% CI = 1.00-2.64; P: =.05) after adjustment. There was an excess of CC genotypes in case subjects who had at least one affected first- or second-degree relative, compared with control subjects unstratified by family history of breast cancer (23% versus 11%; P: =.006), and these case subjects had a threefold to fourfold higher risk than women of other groups defined by genotype and family history of breast cancer. Analysis of breast cancer in first- and second-degree relatives of case subjects with the CC genotype, excluding two known carriers of a deleterious mutation in BRCA1 or BRCA2, gave a relative hazard in women with the CC genotype of 3.48 (95% CI = 1.13-10.74; P: =.04), which is equivalent to a cumulative risk of 16% to age 70 years.Conclusions: The CC genotype may modify the effect of other familial risk factors for early-onset breast cancer. [ABSTRACT FROM AUTHOR]

Published
2000
Full Text
View/download PDF

210. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Kar, S. P., Tyrer, J. P., Li, Qiyuan, Lawrenson, K., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Berchuck, A., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y. A., Chen, Z., Cook, L. S., Cramer, Daniel William, Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J. A., Dork, T., du Bois, A., Durst, M., Eccles, D., Easton, D. F., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y.-T., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goode, E. L., Goodman, M. T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A. T., Hillemanns, P., Hogdall, E., Hogdall, C. K., Hosono, S., Iversen, E. S., Jakubowska, A., Paul, J., Jensen, A., Ji, B.-T., Karlan, B. Y., Kjaer, S. K., Kelemen, L. E., Kellar, M., Kelley, J., Kiemeney, L. A., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I. A., Menon, U., Modugno, F., Moysich, K. B., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Phelan, C. M., Pike, M. C., Poole, Elizabeth M., Ramus, S. J., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schildkraut, J. M., Schwaab, I., Shu, X.-O., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Sucheston-Campbell, L. E., Tangen, I. L., Teo, S.-H., Terry, Kathryn Lynne, Thompson, P. J., Timorek, A., Tsai, Y.-Y., Tworoger, Shelley Slate, van Altena, A. M., Van Nieuwenhuysen, E., Vergote, I., Vierkant, R. A., Wang-Gohrke, S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Woo, Y.-L., Wu, X., Wu, A., Yang, H., Zheng, W., Ziogas, A., Sellers, T. A., Monteiro, A. N. A., Freedman, M. L., Gayther, S. A., and Pharoah, P. D. P.

Subjects
ovarian cancer, network analysis, GWAS, gene expression, transcription factors
Abstract

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Published
2015
Full Text
View/download PDF

211. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author

Johnatty, S. E., Tyrer, J. P., Kar, S., Beesley, J., Lu, Y., Gao, B., Fasching, P. A., Hein, A., Ekici, A. B., Beckmann, M. W., Lambrechts, D., Van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Modugno, F., Ness, R. B., Moysich, K. B., Levine, D. A., Kiemeney, L. A., Massuger, L. F. A. G., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Brinton, L., Lissowska, J., Wentzensen, N., Song, H., Rhenius, V., Campbell, I., Eccles, D., Sieh, W., Whittemore, A. S., McGuire, V., Rothstein, J. H., Sutphen, R., Anton-Culver, H., Ziogas, A., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Pearce, C. L., Pike, M. C., Stram, D. O., Wu, A. H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Rzepecka, I. K., Spiewankiewicz, B., Goodman, M. T., Wilkens, L. R., Carney, M. E., Thompson, P. J., Heitz, F., du Bois, A., Schwaab, I., Harter, P., Pisterer, J., Hillemanns, P., Karlan, B. Y., Walsh, C., Lester, J., Orsulic, S., Winham, S. J., Earp, M., Larson, M. C., Fogarty, Z. C., Hogdall, E., Jensen, A., Kjaer, S. K., Fridley, B. L., Cunningham, J. M., Vierkant, R. A., Schildkraut, J. M., Iversen, E. S., Terry, Kathryn Lynne, Cramer, Daniel William, Bandera, E. V., Orlow, I., Pejovic, T., Bean, Y., Hogdall, C., Lundvall, L., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Sellers, T., Kennedy, C., Chiew, Y.-E., Berchuck, A., MacGregor, S., Pharoah, P. D. P., Goode, E. L., deFazio, A., Webb, P. M., and Chenevix-Trench, G.

Subjects
progression-free survival, overall survival, epithelial ovarian cancer, lncRNA, chemotherapy
Abstract

PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. RESULTS: Five SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)). CONCLUSIONS: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies., Other Research Unit

Published
2015
Full Text
View/download PDF

213. Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer

Author

Lewis, AG, Flanagan, J, Marsh, A, Pupo, GM, Mann, G, Spurdle, AB, Lindeman, GJ, Visvader, JE, Brown, MA, and Chenevix-Trench, G

Abstract

Introduction Mutations in known predisposition genes account for only about a third of all multiple-case breast cancer families. We hypothesized that germline mutations in FANCD2, BRIP1/BACH1, LMO4 and SFN may account for some of the unexplained multiple-case breast cancer families.Methods The families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I).Results DHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity.Conclusion There is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk.

Published
2005

214. No significant association between progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of ovarian cancer.

Author

Spurdle, A B, Webb, P M, Purdie, D M, Chen, X, Green, A, and Chenevix-Trench, G

Abstract

Epidemiological studies suggest that ovarian cancer is an endocrine-related tumour, and progesterone exposure specifically may decrease the risk of ovarian cancer. To assess whether the progesterone receptor (PR) exon 4 valine to leucine amino acid variant is associated with specific tumour characteristics or with overall risk of ovarian cancer, we examined 551 cases of epithelial ovarian cancer and 298 unaffected controls for the underlying G-->T nucleotide substitution polymorphism. Stratification of the ovarian cancer cases according to tumour behaviour (low malignant potential or invasive), histology, grade or stage failed to reveal any heterogeneity with respect to the genotype defined by the PR exon 4 polymorphism. Furthermore, the genotype distribution did not differ significantly between ovarian cancer cases and unaffected controls. Compared with the GG genotype, the age-adjusted odds ratio (95% confidence interval) for risk of ovarian cancer was 0.78 (0.57-1.08) for the GT genotype, and 1.39 (0.47-4.14) for the TT genotype. In conclusion, the PR exon 4 codon 660 leucine variant encoded by the T allele does not appear to be associated with ovarian tumour behaviour, histology, stage or grade. This variant is also not associated with an increased risk of ovarian cancer, and is unlikely to be associated with a large decrease in ovarian cancer risk, although we cannot rule out a moderate inverse association between the GT genotype and ovarian cancer.

Published
2001
Full Text
View/download PDF

215. Polymorphisms at the glutathione S-transferase GSTM1, GSTT1 and GSTP1 loci: risk of ovarian cancer by histological subtype.

Author

Spurdle, A B, Webb, P M, Purdie, D M, Chen, X, Green, A, and Chenevix-Trench, G

Abstract

The phase II glutathione S-transferases (GSTs) GSTT1, GSTM1 and GSTP1 catalyse glutathione-mediated reduction of exogenous and endogenous electrophiles. These GSTs have broad and overlapping substrate specificities and it has been hypothesized that allelic variants associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to cancer. To assess the role of GST gene variants in ovarian cancer development, we screened 285 epithelial ovarian cancer cases and 299 unaffected controls for the GSTT1 deletion (null) variant, the GSTM1 deletion (null) variant and the GSTP1 codon 104 A-->G Ile-->Val amino acid substitution variant. The frequencies of the GSTT1, GSTM1 and GSTP1 polymorphic variants did not vary with tumour behaviour (low malignant potential or invasive) or p53 immunohistochemical status. There was a suggestion that ovarian cancers of the endometrioid or clear cell histological subtype had a higher frequency of the GSTT1 and GSTM1 deletion genotype than other histological subgroups. The GSTT1, GSTM1 and GSTP1 genotype distributions did not differ significantly between unaffected controls and ovarian cancer cases (overall or invasive cancers only). However, the GSTM1 null genotype was associated with increased risk of endometrioid/clear cell invasive cancer [age-adjusted OR (95% CI) = 2.04 (1.01-4.09), P = 0.05], suggesting that deletion of GSTM1 may increase the risk of ovarian cancer of these histological subtypes specifically. This marginally significant finding will require verification by independent studies.

Published
2001
Full Text
View/download PDF

216. Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer.

Author

Bianco, T, Chenevix-Trench, G, Walsh, D C, Cooper, J E, and Dobrovic, A

Abstract

The role of BRCA1 in sporadic breast and ovarian cancers remains elusive. Direct involvement of BRCA1 in the development of breast and ovarian cancer is suggested by the finding that the BRCA1 promoter region CpG island is methylated in a proportion of breast and ovarian cancers. The aim of this study was to compare the incidence of BRCA1 promoter region methylation in tumours in which loss of BRCA1 has been shown to play a role in pathogenesis (breast and ovarian carcinomas) with the incidence in tumours in which BRCA1 is unlikely to play a role in pathogenesis. Promoter region hypermethylation was significantly more common (P < 0.008) in breast and ovarian cancer (6/38 tumours methylated) than in colon cancer (0/35 tumours methylated) or in leukaemias (0/19 samples methylated). The restriction of BRCA1 promoter region hypermethylation to breast and ovarian cancer is consistent with a pathogenetic role of BRCA1 promoter methylation in these tumours. We suggest that the rarity of observed BRCA1 mutations in sporadic breast and ovarian cancer is due to the greater likelihood of BRCA1 inactivation by non-mutational mechanisms such as methylation.

Published
2000
Full Text
View/download PDF

218. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

Author

Manjeet K. Bolla, Carl Blomqvist, Qin Wang, Qi Guo, Melissa C. Southey, Giuseppe Floris, Kristiina Aittomäki, Joe Dennis, Douglas F. Easton, Peter A. Fasching, Sofia Khan, Jenny Chang-Claude, Paul D.P. Pharoah, Jonathan Beesley, Rainer Fagerholm, Diether Lambrechts, Alison M. Dunning, Jianjun Liu, Fiona M. Blows, Päivi Heikkilä, Jonine D. Figueroa, Sabine Behrens, kConFab, Montserrat Garcia-Closas, Irene L. Andrulis, Bernd Holleczek, Aocs Investigators, Maral Jamshidi, Elena Provenzano, Fergus J. Couch, Jani Saarela, Ute Hamann, Michael Lush, Agnes Jager, Renske Keeman, Gord Glendon, Veli-Matti Kosma, Emily Hallberg, Annika Lindblom, Kamila Czene, Matthias W. Beckmann, John L. Hopper, H. Raza Ali, Heli Nevanlinna, Chenevix-Trench G, Maria Kabisch, Arto Mannermaa, Hermann Brenner, Maartje J. Hooning, Marjanka K. Schmidt, Per Hall, Mitul Shah, Sara Margolin, Kyriaki Michailidou, Medical Oncology, School of Medicine / Clinical Medicine, Ali, Raza [0000-0001-7587-0906], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Anthracycline, Quantitative Trait Loci, SNP, Estrogen receptor, Breast Neoplasms, Single-nucleotide polymorphism, Gene mutation, anthracycline, Bioinformatics, Polymorphism, Single Nucleotide, survival, Young Adult, 03 medical and health sciences, breast cancer, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, Anthracyclines, TP53, Survival analysis, Aged, Aged, 80 and over, SKP Cullin F-Box Protein Ligases, Predictive marker, business.industry, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, business, Research Paper
Abstract

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes. In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines. If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer., published version, peerReviewed

Full Text
View/download PDF

219. Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Author

White, K. L., Vierkant, R. A., Fogarty, Z. C., Charbonneau, B., Block, M. S., Pharoah, P. D. P., Chenevix-Trench, G., Rossing, M. A., Cramer, Daniel William, Pearce, C. L., Schildkraut, J. M., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van DenBerg, D., Terry, Kathryn Lynne, Vitonis, A. F., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Sellers, T. A., Phelan, C. M., Kalli, K. R., Cunningham, J. M., Fridley, B. L., and Goode, E. L.

Abstract

Background Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.

Published
2013
Full Text
View/download PDF

220. Risk of Ovarian Cancer and the NF- B Pathway: Genetic Association with IL1A and TNFSF10

Author

Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, Shelley Slate, Poole, Elizabeth M., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, Kathryn Lynne, Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dork, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, Daniel William, Flanagan, J. M., Phelan, C. M., Brown, Robert, Massuger, L. F. A. G., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, Robert R, McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., Van Altena, A. M., van den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A. T., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D. P., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., and Goode, E. L.

Subjects
clear cell, endometrioid, case-control, single nucleotide polymorphism, IL-1α
Abstract

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted., Other Research Unit

Published
2013
Full Text
View/download PDF

221. The Role of KRAS rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing

Author

Pharoah, P. D. P., Palmieri, R. T., Ramus, S. J., Gayther, S. A., Andrulis, I. L., Anton-Culver, H., Antonenkova, N., Antoniou, A. C., Goldgar, D., Beattie, M. S., Beckmann, M. W., Birrer, Michael James, Bogdanova, N., Bolton, K. L., Brewster, W., Brooks-Wilson, A., Brown, R., Butzow, R., Caldes, T., Caligo, M. A., Campbell, I., Chang-Claude, J., Chen, Y. A., Cook, L. S., Couch, F. J., Cramer, Daniel William, Cunningham, J. M., Despierre, E., Doherty, J. A., Dork, T., Durst, M., Eccles, D. M., Ekici, A. B., Easton, D., Fasching, P. A., de Fazio, A., Fenstermacher, D. A., Flanagan, J. M., Fridley, B. L., Friedman, E., Gao, B., Sinilnikova, O., Gentry-Maharaj, A., Godwin, A. K., Goode, E. L., Goodman, M. T., Gross, J., Hansen, T. V. O., Harnett, P., Rookus, M., Heikkinen, T., Hein, R., Hogdall, C., Hogdall, E., Iversen, E. S., Jakubowska, A., Johnatty, S. E., Karlan, B. Y., Kauff, N. D., Kaye, S. B., Chenevix-Trench, G., Kelemen, L. E., Kiemeney, L. A., Kjaer, S. K., Lambrechts, D., LaPolla, J. P., Lazaro, C., Le, N. D., Leminen, A., Leunen, K., Levine, D. A., Lu, Y., Lundvall, L., Macgregor, S., Marees, T., Massuger, L. F., McLaughlin, J. R., Menon, U., Montagna, M., Moysich, K. B., Narod, S. A., Nathanson, K. L., Nedergaard, L., Ness, R. B., Nevanlinna, H., Nickels, S., Osorio, A., Paul, J., Pearce, C. L., Phelan, C. M., Pike, M. C., Radice, P., Rossing, M. A., Schildkraut, J. M., Sellers, T. A., Singer, C. F., Song, H., Stram, D. O., Sutphen, R., Lindblom, A., Terry, Kathryn Lynne, Tsai, Y.-Y., van Altena, A. M., Vergote, I., Vierkant, R. A., Vitonis, A. F., Walsh, C., Wang-Gohrke, S., Wappenschmidt, B., Wu, A. H., Ziogas, A., Berchuck, A., and Risch, H. A.

Abstract

Purpose An assay for the single nucleotide polymorphism (SNP) rs61764370 has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′UTR miRNA binding site of the KRAS oncogene, and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published paper, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from nineteen studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival data and eighteen studies with all-cause mortality data. Results No evidence of association was observed between genotype and risk of unselected EOC (odds ratio (OR)=1.02, 95% confidence interval (CI)=0.95–1.10), serous EOC (OR=1.08, 95%CI=0.98–1.18), familial EOC (OR=1.09, 95%CI=0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR=1.09, 95%CI=0.88–1.36). There was little evidence for association with survival time among unselected cases (hazard ratio (HR)=1.10, 95%CI=0.99–1.22), among serous cases (HR=1.12, 95%CI=0.99–1.28), or with progression-free survival in 540 cases treated with carboplatin and paclitaxel (HR=1.18, 95%CI=0.93–1.52). Conclusions These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction therefore appears unwarranted.

Published
2011
Full Text
View/download PDF

222. Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer

Author

Amankwah, E. K., Kelemen, L. E., Wang, Q., Song, H., Chenevix-Trench, G., Beesley, J., Webb, P. M., Pearce, C. L., Wu, A. H., Pike, M. C., Stram, D. O., Chang-Claude, J., Wang-Gohrke, S., Ness, R. B., Goode, E. L., Cunningham, J. M., Fridley, B. L., Vierkant, R. A., Tworoger, Shelley Slate, Whittemore, A. S., McGuire, V., Sieh, W., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Rossing, M. A., Doherty, J. A., Goodman, M. T., Carney, M. E., Lurie, G., Wilkens, L. R., Kruger Kjaer, S., Hogdall, E., Cramer, Daniel William, Terry, Kathryn Lynne, Garcia-Closas, M., Yang, H., Lissowska, J., Anton-Culver, H., Ziogas, A., Schildkraut, J. M., Berchuck, A., and Pharoah, P. D. P.

Subjects
chromosome 3p, SNP, ovarian cancer, risk factors
Abstract

Background We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC) [odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4, Ptrend=0.01] that showed a stronger association with the serous histological subtype (OR=1.3, 95% CI=1.1-1.5, Ptrend=0.003). Methods We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium. Results No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.61; serous: OR=1.0, 95% CI=0.9-1.1, Ptrend=0.85) or from the combined analysis of discovery and replication studies (all: OR=1.0, 95% CI=1.0-1.1, Ptrend= 0.28; serous: OR=1.1, 95% CI=1.0-1.2, Ptrend=0.11). There was no evidence for statistical heterogeneity in ORs across the studies. Conclusions Although rs2660753 is a strong a prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study. Impact Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.

Published
2011
Full Text
View/download PDF

223. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author

Stevens, K N, Garcia-Closas, M, Fredericksen, Z, Kosel, M, Pankratz, V S, Hopper, J L, Dite, G S, Apicella, C, Southey, M C, Schmidt, M K, Broeks, A, Van ‘t Veer, L J, Tollenaar, R A E M, Fasching, P A, Beckmann, M W, Hein, A, Ekici, A B, Johnson, N, Peto, J, dos Santos Silva, I, Gibson, L, Sawyer, E, Tomlinson, I, Kerin, M J, Chanock, S, Lissowska, J, Hunter, David J., Hoover, R N, Thomas, G D, Milne, R L, Pérez, JI Arias, González-Neira, A, Benítez, J, Burwinkel, B, Meindl, A, Schmutzler, R K, Bartrar, C R, Hamann, U, Ko, Y D, Brüning, T, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Dörk, T, Schürmann, P, Bremer, M, Hillemanns, P, Bogdanova, N, Zalutsky, J V, Rogov, Y I, Antonenkova, N, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chenevix-Trench, G, Chen, X, Peterlongo, P, Bonanni, B, Bernard, L, Manoukian, S, Wang, X, Cerhan, J, Vachon, C M, Olson, J, Giles, G G, Baglietto, L, McLean, C A, Severi, G, John, E M, Miron, Alexander, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, I, Knight, J A, Glendon, G, Mulligan, A M, Cox, A, Brock, I W, Elliott, G, Cross, S S, Pharoah, P P, Dunning, A M, Pooley, K A, Humphreys, M K, Wang, J, Kang, D, Yoo, K-Y, Noh, D-Y, Sangrajrang, S, Gabrieau, V, Brennan, P, McKay, J, Anton-Culver, H, Ziogas, A, Couch, F J, and Easton, D F

Subjects
genetic susceptibility, neoplasms, association study
Abstract

Background: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. Methods: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). Results: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95–0.99, P=4.6 × \(10^{−3}\)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96–1.01, P=0.139). Conclusion: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Published
2011
Full Text
View/download PDF

224. Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium

Author

Kelemen, L. E., Goodman, M. T., McGuire, V., Rossing, M. A., Webb, P. M., Kobel, M., Anton-Culver, H., Beesley, J., Berchuck, A., Brar, S., Carney, M. E., Chang-Claude, J., Chenevix-Trench, G., Cramer, Daniel William, Cunningham, J. M., DiCioccio, R. A., Doherty, J. A., Easton, D. F., Fredericksen, Z. S., Fridley, B. L., Gates, M. A., Gayther, S. A., Gentry-Maharaj, A., Hogdall, E., Kjaer, S. K., Lurie, G., Menon, U., Moorman, P. G., Moysich, K., Ness, R. B., Palmieri, R. T., Pearce, C. L., Pharoah, P. D. P., Ramus, S. J., Song, H., Stram, D. O., Tworoger, Shelley Slate, Van Den Berg, D., Vierkant, R. A., Wang-Gohrke, S., Whittemore, A. S., Wilkens, L. R., Wu, A. H., Schildkraut, J. M., Sellers, T. A., and Goode, E. L.

Abstract

Background We previously reported risks of ovarian carcinoma for common polymorphisms in one-carbon (1-C) transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990 and TYMS rs495139 with risk of ovarian carcinoma overall, and to utilize the large sample of assembled cases to investigate associations by histological type. Methods Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site. Results The five polymorphisms were not associated with ovarian carcinoma overall (P trend > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04) and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04) (P heterogeneity = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05). Conclusions TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathological classification. Impact Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology. Additional genotyping in a larger sample with increased gene coverage is underway.

Published
2010
Full Text
View/download PDF

225. Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

Author

Schildkraut, J. M., Goode, E. L., Clyde, M. A., Iversen, E. S., Moorman, P. G., Berchuck, A., Marks, J. R., Lissowska, J., Brinton, L., Peplonska, B., Cunningham, J. M., Vierkant, R. A., Rider, D. N., Chenevix-Trench, G., Webb, P. M., Beesley, J., Chen, X., Phelan, C., Sutphen, R., Sellers, T. A., Pearce, L., Wu, A. H., Van Den Berg, D., Conti, D., Elund, C. K., Anderson, R., Goodman, M. T., Lurie, G., Carney, M. E., Thompson, P. J., Gayther, S. A., Ramus, S. J., Jacobs, I., Kruger Kjaer, S., Hogdall, E., Blaakaer, J., Hogdall, C., Easton, D. F., Song, H., Pharoah, P. D.P., Whittemore, A. S., McGuire, V., Quaye, L., Anton-Culver, H., Ziogas, A., Terry, Kathryn Lynne, Cramer, Daniel William, Hankinson, Susan Elizabeth, Tworoger, Shelley Slate, Calingaert, B., Chanock, S., Sherman, M., and Garcia-Closas, M.

Subjects
TP53, polymorphisms, ovarian cancer, epidemiology
Abstract

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNPs) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (ORs), 95% probability intervals (PIs) and Bayes factors (BFs) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR = 1.30; 95% PI = 1.07-1.57) and rs12951053 (median per allele OR = 1.19; 95% PI = 1.01 - 1.38). Analyses of other histological subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.

Published
2009
Full Text
View/download PDF

226. Exploring the link between MORF4L1 and risk of breast cancer

Author

Martrat, G., Maxwell, C.A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuhl, J., Neveling, K., Schindler, D., Ramirez, M.J., Castella, M., Hernandez, G., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Platte, R., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K.R., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A.L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X.Q., Beesley, J., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Asperen, C.J., Bodmer, D., Ausems, M.G.E.M., Os, T.A. van, Blok, M.J., Meijers-Heijboer, H.E.J., Hogervorst, F.B.L., Goldgar, D.E., Buys, S., John, E.M., Miron, A., Southey, M., Daly, M.B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., Friedman, E., Domchek, S.M., Nathanson, K.L., Rebbeck, T.R., Oskar, T., Couch, F.J., Wang, X.S., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F.K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M.A., Godwin, A.K., Imyanitov, E.N., Janavicius, R., Sinilnikova, O.M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., Pauw, A. de, Bignon, Y.J., Uhrhammer, N., Peyrat, J.P., Vennin, P., Ferrer, S.F., Collonge-Rame, M.A., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O.M., Antoniou, A.C., Ceron, J., Tominaga, K., Surralles, J., Pujana, M.A., EMBRACE, kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Human Genetics, BMC, Ed., Translational Research Laboratory, Catalan Institute of Oncology-Bellvitge Institute for Biomedical Research, Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Catalan Institute of Oncology, Department of Cellular and Structural Biology, The University of Texas Health Science Center at Houston (UTHealth)-Sam and Ann Barshop Institute for Longevity and Aging Studies, Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Biomarkers and Susceptibility Unit, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Biomedical Research Centre Network for Rare Diseases (CIBERER), Genetic Counseling and Hereditary Cancer Programme, Section of Cancer Genetics, Institute of cancer research, Department of Human Genetics, Julius-Maximilians-Universität Würzburg (JMU), Strangeways Research Laboratory, University of Cambridge [UK] (CAM)-Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, Centre for Cancer Genetic Epidemiology [Cambridge], University of Cambridge [UK] (CAM)-Department of Oncology, Genetic Medicine, St Mary's Hospital-NHS Foundation Trust-Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Clinical Genetics Department, Guy's and St Thomas NHS Foundation Trust, Yorkshire Regional Genetics Service, St James's hospital, Ferguson-Smith Centre for Clinical Genetics, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Institute of Human Genetics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Queen Mary University of London (QMUL)-St George's Hospital, Department of Clinical Genetics, Royal Devon & Exeter Hospital, Northern Ireland Regional Genetics Centre, Belfast City Hospital, South East of Scotland Regional Genetics Service, Western General Hospital, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine-Fondazione IRCCS Istituto Nazionale Tumori (INT), Department of Preventive and Predictive Medicine, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Fondazione IRCCS INT, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Division of Experimental Oncology 1, Centro di Riferimento Oncologico (CRO), Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Firenze = University of Florence (UniFI), Fiorgen Foundation for Pharmacogenomics, Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, IEO, Division of Genetics and Population Health, Queensland Institute of Medical Research, Department of Epidemiology, The Netherlands Cancer Institute, Family Cancer Clinic, Department of Surgical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), DNA Diagnostics, Radboud University Medical Center [Nijmegen], Department of Medical Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), University Hospital Maastricht, VU Medical Center, Department of Dermatology, University of Utah School of Medicine [Salt Lake City], Department of Internal Medicine, Huntsman Cancer Institute, Cancer Prevention Institute of California, Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Surgery, Harvard Medical School [Boston] (HMS), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (MEGA), University of Melbourne-Melbourne School of Population Health, Division of Population Science, Fox Chase Cancer Center, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Karolinska University Hospital [Stockholm], Department of Genetics and Pathology, Uppsala University, Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, The Institute of Oncology, Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Sackler Faculty of Medicine, Tel Aviv University (TAU), Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Department of Medicine, Medical Genetics, Abramson Cancer Center-Perelman School of Medicine, Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland [Reykjavik], Department of Laboratory Medicine and Pathology, Mayo Clinic, Department of Health Sciences Research, Statistical Assessment Service, Department of Physiology, Universität zu Lübeck = University of Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, Medical Oncology Branch, Hospital Clínico San Carlos, Human Cancer Genetics Programme, CIBER de Enfermedades Raras (CIBERER)-Spanish National Cancer Research Centre, Division of Hematopoiesis and Gene Therapy, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas [Madrid] (CIEMAT), Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Instituto de Genética Humana, Pontificia Universidad Javeriana (PUJ), Section of Genetic Oncology, University of Pisa - Università di Pisa, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Kansas City, KS, USA], Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion, Vilnius University [Vilnius]-Hospital Santariskiu Clinics, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Oncologique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Consultation d'Oncogénétique, Laboratoire de Génétique Chromosomique, CH Chambéry, Département de Génétique et Reproduction, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, The CIMBA data management is supported by Cancer Research - UK., kConFab, HEBON, BCFR, SWE-BRCA, GEMO Study Collaborators, Autonomous University of Barcelona, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Department of Oncology-University of Cambridge [UK] (CAM), University of Turin, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Tel Aviv University [Tel Aviv], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universität zu Lübeck [Lübeck]-Center for Structural and Cell Biology in Medicine, University of Kansas Medical Center [Lawrence], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Universiteit Leiden-Universiteit Leiden, Skåne University Hospital-Lund University [Lund], University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Faculteit der Geneeskunde, Klinische Genetica, RS: GROW - School for Oncology and Reproduction, Genetica & Celbiologie, Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Martrat, G, Maxwell, C, Tominaga, E, Porta de la Riva, M, Bonifaci, N, Gómez Baldó, L, Bogliolo, M, Lázaro, C, Blanco, I, Brunet, J, Aguilar, H, Fernández Rodríguez, J, Seal, S, Renwick, A, Rahman, N, Kühl, J, Neveling, K, Schindler, D, Ramírez, M, Castellà, M, Hernández, G, Embrace, Easton, D, Peock, S, Cook, M, Oliver, C, Frost, D, Platte, R, Evans, D, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Davidson, R, Ong, K, Cook, J, Douglas, F, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Pasini, B, Ottini, L, Putignano, A, Savarese, A, Bernard, L, Radice, P, Healey, S, Spurdle, A, Chen, X, Beesley, J, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Asperen, C, Bodmer, D, Ausems, M, van Os, T, Blok, M, Meijers Heijboer, H, Hogervorst, F, Goldgar, D, Buys, S, John, E, Miron, A, Southey, M, Daly, M, Harbst, K, Borg, A, Rantala, J, Barbany Bustinza, G, Ehrencrona, H, Stenmark Askmalm, M, Kaufman, B, Laitman, Y, Milgrom, R, Friedman, E, Domchek, S, Nathanson, K, Rebbeck, T, Johannsson, O, Couch, F, Wang, X, Fredericksen, Z, Cuadras, D, Moreno, V, Pientka, F, Depping, R, Caldés, T, Osorio, A, Benítez, J, Bueren, J, Heikkinen, T, Nevanlinna, H, Hamann, U, Torres, D, Caligo, M, Godwin, A, Imyanitov, E, Janavicius, R, Sinilnikova, O, Stoppa Lyonnet, D, Mazoyer, S, Verny Pierre, C, Castera, L, de Pauw, A, Bignon, Y, Uhrhammer, N, Peyrat, J, Vennin, P, Ferrer, S, Collonge Rame, M, Mortemousque, I, Mcguffog, L, Chenevix Trench, G, Pereira Smith, O, Antoniou, A, Cerón, J, Tominaga, K, Surrallés, J, Pujana, M, Human genetics, CCA - Oncogenesis, Biomedical Research Centre Network for Epidemiology and Public Health ( CIBERESP ), The University of Texas Health Science Center at San Antonio-Sam and Ann Barshop Institute for Longevity and Aging Studies, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] ( IDIBELL ), Biomedical Research Centre Network for Rare Diseases ( CIBERER ), University of Würzburg, University of Cambridge [UK] ( CAM ) -Department of Public Health and Primary Care-Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] ( CAM ) -Department of Oncology, Birmingham Women's Hospital Healthcare NHS Trust, Sheffield Children's Hospital, Newcastle Upon Tyne Hospitals NHS Trust, Queen Mary University of London ( QMUL ) -St George's Hospital, IFOM, Istituto FIRC di Oncologia Molecolare ( IFOM ), Università degli Studi di Roma 'La Sapienza' [Rome], University of Florence, Erasmus MC-Daniel den Hoed Cancer Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Harvard Medical School [Boston] ( HMS ), Centre for Molecular, Environmental, Genetic and Analytic Epidemiology ( MEGA ), University of Pennsylvania School of Medicine, University of Pennsylvania School of Medicine-Abramson Cancer Center, Centro de Investigaciones Energéticas, Deutsches Krebsforschungszentrum ( DKFZ ), Pontificia Universidad Javeriana, University of Pisa [Pisa], University of Kansas Medical Center, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), INSTITUT CURIE, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Jean Perrin, CRLCC Oscar Lambret, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Hôpital Bretonneau-CHRU Tours, and Universitat de Barcelona

Subjects
DNA Repair, Genes, BRCA2, RAD51, Genes, BRCA1, Germ-Cell, Helicase Brip1, medicine.disease_cause, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 0302 clinical medicine, Breast cancer, Fanconi anemia, Risk Factors, Replication Protein A, Teknik och teknologier, Homologous Recombination, skin and connective tissue diseases, C-Elegans, Genetics, Medicine(all), ddc:616, 0303 health sciences, Mutation, Fanconi Anemia Complementation Group D2 Protein, Nuclear Proteins, Anèmia aplàstica, 3. Good health, 030220 oncology & carcinogenesis, Chromodomain Protein, Engineering and Technology, Female, RNA Interference, Fanconi Anemia Complementation Group N Protein, Aplastic anemia, Research Article, BRCA2 Mutation Carrier, DNA repair, PALB2, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cell Line, Càncer de mama, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.CAN] Life Sciences [q-bio]/Cancer, Two-Hybrid System Techniques, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Caenorhabditis elegans, Gene, 030304 developmental biology, Phenocopy, Caenorhabditis-Elegan, Tumor Suppressor Proteins, medicine.disease, BRCA1, BRCA2, Pancreatic-Cancer, Fanconi Anemia, Genes, Cancer and Oncology, Fanconi-Anemia, Cancer research, Rad51 Recombinase, Susceptibility Gene, DNA Damage, Transcription Factors
Abstract

Introduction Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

228. Short communications. Urokinase receptor genotypes in colorectal cancer.

Author

Kohonen-Corish, M, Young, J, Chenevix-Trench, G, and Doe, WF

Abstract

A previous study has reported a high frequency of rare alleles of the urokinase-type plasminogen activator receptor (uPAR) in a set of 15 colorectal cancer (CRC) cell lines. Our study investigated uPAR gene variation in 92 CRC patients and in tumour DNA from a subset of 69 patients using the PLAUR-IVS3 marker located in an intron of this gene. The overall distribution of the marker alleles in the patients did not differ significantly from a set of 105 controls. A pairwise analysis of individual allele frequencies showed, however, that the common allele 147 was significantly decreased (P = 0.027) and allele 149 was significantly increased (P = 0.033) in the patients. These results may indicate an effect of uPAR gene variation in CRC carcinogenesis and encourages further examination of this marker in an independent series of patients. [ABSTRACT FROM PUBLISHER]

Published
1998
Full Text
View/download PDF

231. Frequent loss of heterozygosity on chromosome 18 in ovarian adenocarcinoma which does not always include the DCC locus

Author

Chenevix-Trench G, Leary J, Kerr J, Michel J, Kefford R, Hurst T, Peter Parsons, Friedlander M, and Sk, Khoo

Subjects
Ovarian Neoplasms, Heterozygote, Chromosome Mapping, Humans, Female, Genes, Tumor Suppressor, Adenocarcinoma, Chromosome Deletion, Chromosomes, Human, Pair 18, DNA Probes, Chromosome Banding, Neoplasm Staging
Abstract

Inactivation of the DCC gene on chromosome 18 owing to loss of heterozygosity is a common finding in colorectal cancer. Because both ovarian and colon cancer are features of Lynch syndrome II, which has been provisionally mapped to chromosome 18, we hypothesized that loss of heterozygosity at the DCC locus may also occur in ovarian neoplasia. Fifty-two sporadic ovarian adenocarcinoma tumours were analysed by Southern blotting for loss of heterozygosity (LOH) at six chromosome 18 loci. Overall, tumours from 31 patients (60%) showed allelic loss at one or more of these loci. A similarly high level of LOH, 66%, was found at D17S5 (17p13.3). In contrast, moderate levels of LOH, of 31%, 39% and 33%, were found at MYCL1 (1p32), D1S57 (1p) and D14S20 (14q32.33) respectively. However, analysis of partial chromosome deletions in 11 patients indicates that the smallest region of overlap appears to exclude the DCC gene but to be between the D18S5 and D18S11 loci. This suggests that another locus, as well as or apart from DCC, may be involved.

233. Rare variants in the ATM gene and risk of breast cancer

Author

Goldgar, D. E., Healey, S., Dowty, J. G., Da Silva, L., Chen, X., Spurdle, A. B., Terry, M. B., Daly, M. J., Buys, S. M., Southey, M. C., Andrulis, I., John, E. M., Khanna, K. K., Hopper, J. L., Oefner, Peter J., Lakhani, S., and Chenevix-Trench, G.

Subjects
610 Medizin, 3. Good health
Abstract

INTRODUCTION: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved. METHODS: To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants. RESULTS: In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant. CONCLUSIONS: The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.

234. A large, dominant pedigree of atrioventricular septal defect (AVSD): exclusion from the Down syndrome critical region on chromosome 21

Author

Wilson L, Curtis A, Jr, Korenberg, Rd, Schipper, Allan L, Chenevix-Trench G, Stephenson A, Goodship J, and John Burn

Subjects
Adult, Genetic Markers, Male, congenital, hereditary, and neonatal diseases and abnormalities, Polymorphism, Genetic, Genotype, Chromosomes, Human, Pair 21, Genetic Linkage, Heart Septal Defects, Infant, Middle Aged, Pedigree, Autoradiography, Humans, Electrophoresis, Polyacrylamide Gel, Female, Down Syndrome, Lod Score, Child, Aged, Research Article
Abstract

We describe a large pedigree of individuals with autosomal dominant atrioventricular septal defect (AVSD). The pedigree includes affected individuals and individuals who have transmitted the defect but are not clinically affected. AVSDs are a rare congenital heart malformation that occurs as only 2.8% of isolated cardiac lesions. They are the predominant heart defect in children with Down syndrome, making chromosome 21 a candidate for genes involved in atrioventricular septal development. We have carried out a linkage study in the pedigree by using 10 simple-sequence polymorphisms from chromosome 21. Multipoint linkage analysis gives lod scores of less than -2 for the region of trisomy 21 associated with heart defects, which excludes a locus within this region as the cause of the defect in this family.

235. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Author

Lei, J, Rudolph, A, Moysich, KB, Rafiq, S, Behrens, S, Goode, EL, Pharoah, PD, Seibold, P, Fasching, PA, Andrulis, IL, Kristensen, VN, Couch, FJ, Hamann, U, Hooning, MJ, Nevanlinna, H, Eilber, U, Bolla, MK, Dennis, J, Wang, Q, Lindblom, A, Mannermaa, A, Lambrechts, D, García-Closas, M, Hall, P, Chenevix-Trench, G, Shah, M, Luben, R, Haeberle, L, Ekici, AB, Beckmann, MW, Knight, JA, Glendon, G, Tchatchou, S, Alnæs, GI, Borresen-Dale, AL, Nord, S, Olson, JE, Hallberg, E, Vachon, C, Torres, D, Ulmer, HU, Rüdiger, T, Jager, A, Van Deurzen, CH, Tilanus-Linthorst, MM, Muranen, TA, Aittomäki, K, Blomqvist, C, Margolin, S, Kosma, VM, Hartikainen, JM, Kataja, V, Hatse, S, Wildiers, H, Smeets, A, Figueroa, J, Chanock, SJ, Lissowska, J, Li, J, Humphreys, K, Phillips, KA, KConFab Investigators, Linn, S, Cornelissen, S, Van Den Broek, SA, Kang, D, Choi, JY, Park, SK, Yoo, KY, Hsiung, CN, Wu, PE, Hou, MF, Shen, CY, Teo, SH, Taib, NA, Yip, CH, Ho, GF, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Dunning, AM, Benitez, J, Czene, K, Sucheston, LE, Maishman, T, Tapper, WJ, Eccles, D, Easton, DF, Schmidt, MK, and Chang-Claude, J

Subjects
Adult, 32 Biomedical and Clinical Sciences, Breast Neoplasms, Kaplan-Meier Estimate, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Immunomodulation, Breast Cancer, Antineoplastic Combined Chemotherapy Protocols, Genetics, Biomarkers, Tumor, 2.1 Biological and endogenous factors, Humans, Cancer, Neoplasm Staging, 2 Aetiology, Interleukin-12 Subunit p40, Receptor, Transforming Growth Factor-beta Type II, Genomics, Middle Aged, 3211 Oncology and Carcinogenesis, Prognosis, 3. Good health, Tumor Burden, 3204 Immunology, Treatment Outcome, Receptors, Estrogen, FOS: Biological sciences, Female, Neoplasm Grading, 4 Detection, screening and diagnosis, Receptors, Transforming Growth Factor beta, 4.2 Evaluation of markers and technologies, Signal Transduction
Abstract

Tumor lymphocyte infiltration has been associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied invasive breast cancer patients of European ancestry with stage I-III disease, including 9,334 ER-positive patients (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).

238. Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers

Author

Walker, LC, Marquart, L, Pearson, JF, Wiggins, GAR, O'Mara, TA, Parsons, MT, BCFR, Barrowdale, D, McGuffog, L, Dennis, J, Benitez, J, Slavin, TP, Radice, P, Frost, D, EMBRACE, Godwin, AK, Meindl, A, Schmutzler, RK, GEMO Study Collaborators, Isaacs, C, Peshkin, BN, Caldes, T, Hogervorst, FB, HEBON, Lazaro, C, Jakubowska, A, Montagna, M, KConFab Investigators, Chen, X, Offit, K, Hulick, PJ, Andrulis, IL, Lindblom, A, Nussbaum, RL, Nathanson, KL, Chenevix-Trench, G, Antoniou, AC, Couch, FJ, and Spurdle, AB

Subjects
Adult, Glutamate Carboxypeptidase II, Ovarian Neoplasms, Heterozygote, Genes, Modifier, endocrine system diseases, DNA Copy Number Variations, BRCA1 Protein, Pregnancy-Specific beta 1-Glycoproteins, Breast Neoplasms, 3. Good health, DNA-Binding Proteins, Transcription Factors, TFII, Humans, Female, Aryl Hydrocarbon Hydroxylases, Cytochrome P450 Family 2
Abstract

Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P

239. Frequent loss of heterozygosity on chromosome 14 occurs in advanced colorectal carcinomas

Author

Young J, Barbara Leggett, Ward M, Thomas L, Buttenshaw R, Searle J, and Chenevix-Trench G

Subjects
Adenoma, Chromosomes, Human, Pair 14, Heterozygote, Carcinoma, Mutation, Humans, Adenocarcinoma, Chromosome Deletion, Colorectal Neoplasms, Proto-Oncogene Mas
Abstract

The current model for colorectal tumorigenesis defines four specific mutations (activation of a ras proto-oncogene and inactivation of the APC, p53 and DCC tumor-suppressor genes) that accumulate in a colonic epithelial cell as it progresses towards a carcinoma. However, further mutations must be needed for progression to malignancy because advanced adenomas have been observed with all four of these mutations. Loss of heterozygosity (LOH) for 11 loci spanning the distal portion of the long arm of chromosome 14 was studied in 89 sporadic colorectal adenocarcinomas and 25 adenomas. The overall rate of LOH in carcinomas was 53% (46/86 informative carcinomas). The smallest region of overlap (SRO) of deletions includes the markers D14S19 to D14S20. No LOH was seen in the 18 informative adenomas examined. There was a significant trend towards higher levels of LOH within the SRO in advanced Dukes' stages (P = 0.016). Since frequent loss of heterozygosity in a specific region of a chromosome may reflect the inactivation of a tumor-suppressor gene located there, these data suggest that a gene involved in the progression of colonic neoplasia may reside on the distal portion of the long arm of chromosome 14, and that its inactivation may be a critical event in this process.

240. Prognostic gene expression signature for high-grade serous ovarian cancer

Author

Millstein, J, Budden, T, Goode, EL, Anglesio, MS, Talhouk, A, Intermaggio, MP, Leong, HS, Chen, S, Elatre, W, Gilks, B, Nazeran, T, Volchek, M, Bentley, RC, Wang, C, Chiu, DS, Kommoss, S, Leung, SCY, Senz, J, Lum, A, Chow, V, Sudderuddin, H, Mackenzie, R, George, J, AOCS Group, Fereday, S, Hendley, J, Traficante, N, Steed, H, Koziak, JM, Köbel, M, McNeish, IA, Goranova, T, Ennis, D, Macintyre, G, Silva De Silva, D, Ramón Y Cajal, T, García-Donas, J, Hernando Polo, S, Rodriguez, GC, Cushing-Haugen, KL, Harris, HR, Greene, CS, Zelaya, RA, Behrens, S, Fortner, RT, Sinn, P, Herpel, E, Lester, J, Lubiński, J, Oszurek, O, Tołoczko, A, Cybulski, C, Menkiszak, J, Pearce, CL, Pike, MC, Tseng, C, Alsop, J, Rhenius, V, Song, H, Jimenez-Linan, M, Piskorz, AM, Gentry-Maharaj, A, Karpinskyj, C, Widschwendter, M, Singh, N, Kennedy, CJ, Sharma, R, Harnett, PR, Gao, B, Johnatty, SE, Sayer, R, Boros, J, Winham, SJ, Keeney, GL, Kaufmann, SH, Larson, MC, Luk, H, Hernandez, BY, Thompson, PJ, Wilkens, LR, Carney, ME, Trabert, B, Lissowska, J, Brinton, L, Sherman, ME, Bodelon, C, Hinsley, S, Lewsley, LA, Glasspool, R, Banerjee, SN, Stronach, EA, Haluska, P, Ray-Coquard, I, Mahner, S, Winterhoff, B, Slamon, D, Levine, DA, Kelemen, LE, Benitez, J, Chang-Claude, J, Gronwald, J, Wu, AH, Menon, U, Goodman, MT, Schildkraut, JM, Wentzensen, N, Brown, R, Berchuck, A, Chenevix-Trench, G, DeFazio, A, Gayther, SA, García, MJ, Henderson, MJ, Rossing, MA, Beeghly-Fadiel, A, Fasching, PA, Orsulic, S, Karlan, BY, Konecny, GE, Huntsman, DG, Bowtell, DD, Brenton, JD, Doherty, JA, Pharoah, PDP, and Ramus, SJ

Subjects
Ovarian Neoplasms, high-grade serous ovarian cancer, overall survival, gene expression, Humans, Female, prognosis, formalin-fixed paraffin-embedded, Transcriptome, Survival Analysis, 3. Good health, Cystadenocarcinoma, Serous, Proportional Hazards Models
Abstract

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

241. Association analysis identifies 65 new breast cancer risk loci

Author

Michailidou, K, Lindström, S, Dennis, J, Beesley, J, Hui, S, Kar, S, Lemaçon, A, Soucy, P, Glubb, D, Rostamianfar, A, Bolla, MK, Wang, Q, Tyrer, J, Dicks, E, Lee, A, Wang, Z, Allen, J, Keeman, R, Eilber, U, French, JD, Qing Chen, X, Fachal, L, McCue, K, McCart Reed, AE, Ghoussaini, M, Carroll, JS, Jiang, X, Finucane, H, Adams, M, Adank, MA, Ahsan, H, Aittomäki, K, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Arun, B, Auer, PL, Bacot, F, Barrdahl, M, Baynes, C, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Brinton, L, Broberg, P, Brock, IW, Broeks, A, Brooks-Wilson, A, Brucker, SY, Brüning, T, Burwinkel, B, Butterbach, K, Cai, Q, Cai, H, Caldés, T, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chan, TL, David Cheng, T-Y, Seng Chia, K, Choi, J-Y, Christiansen, H, Clarke, CL, NBCS Collaborators, Collée, M, Conroy, DM, Cordina-Duverger, E, Cornelissen, S, Cox, DG, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Devilee, P, Doheny, KF, Dörk, T, Dos-Santos-Silva, I, Dumont, M, Durcan, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Elvira, M, Engel, C, Eriksson, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fritschi, L, Gaborieau, V, Gabrielson, M, Gago-Dominguez, M, Gao, Y-T, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Georgoulias, V, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grenaker Alnæs, GI, Grip, M, Gronwald, J, Grundy, A, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hamel, N, Hankinson, S, Harrington, P, Hart, SN, Hartikainen, JM, Hartman, M, Hein, A, Heyworth, J, Hicks, B, Hillemanns, P, Ho, DN, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Hou, M-F, Hsiung, C-N, Huang, G, Humphreys, K, Ishiguro, J, Ito, H, Iwasaki, M, Iwata, H, Jakubowska, A, Janni, W, John, EM, Johnson, N, Jones, K, Jones, M, Jukkola-Vuorinen, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kang, D, Kasuga, Y, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kim, S-W, Knight, JA, Kosma, V-M, Kristensen, VN, Krüger, U, Kwong, A, Lambrechts, D, Le Marchand, L, Lee, E, Lee, MH, Lee, JW, Neng Lee, C, Lejbkowicz, F, Li, J, Lilyquist, J, Lindblom, A, Lissowska, J, Lo, W-Y, Loibl, S, Long, J, Lophatananon, A, Lubinski, J, Luccarini, C, Lux, MP, Ma, ESK, MacInnis, RJ, Maishman, T, Makalic, E, Malone, KE, Kostovska, IM, Mannermaa, A, Manoukian, S, Manson, JE, Margolin, S, Mariapun, S, Martinez, ME, Matsuo, K, Mavroudis, D, McKay, J, McLean, C, Meijers-Heijboer, H, Meindl, A, Menéndez, P, Menon, U, Meyer, J, Miao, H, Miller, N, Taib, NAM, Muir, K, Mulligan, AM, Mulot, C, Neuhausen, SL, Nevanlinna, H, Neven, P, Nielsen, SF, Noh, D-Y, Nordestgaard, BG, Norman, A, Olopade, OI, Olson, JE, Olsson, H, Olswold, C, Orr, N, Pankratz, VS, Park, SK, Park-Simon, T-W, Lloyd, R, Perez, JIA, Peterlongo, P, Peto, J, Phillips, K-A, Pinchev, M, Plaseska-Karanfilska, D, Prentice, R, Presneau, N, Prokofyeva, D, Pugh, E, Pylkäs, K, Rack, B, Radice, P, Rahman, N, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Romm, J, Ruddy, KJ, Rüdiger, T, Rudolph, A, Ruebner, M, Rutgers, EJT, Saloustros, E, Sandler, DP, Sangrajrang, S, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schürmann, P, Scott, RJ, Scott, C, Seal, S, Seynaeve, C, Shah, M, Sharma, P, Shen, C-Y, Sheng, G, Sherman, ME, Shrubsole, MJ, Shu, X-O, Smeets, A, Sohn, C, Southey, MC, Spinelli, JJ, Stegmaier, C, Stewart-Brown, S, Stone, J, Stram, DO, Surowy, H, Swerdlow, A, Tamimi, R, Taylor, JA, Tengström, M, Teo, SH, Beth Terry, M, Tessier, DC, Thanasitthichai, S, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Tong, L, Torres, D, Truong, T, Tseng, C-C, Tsugane, S, Ulmer, H-U, Ursin, G, Untch, M, Vachon, C, Van Asperen, CJ, Van Den Berg, D, Van Den Ouweland, AMW, Van Der Kolk, L, Van Der Luijt, RB, Vincent, D, Vollenweider, J, Waisfisz, Q, Wang-Gohrke, S, Weinberg, CR, Wendt, C, Whittemore, AS, Wildiers, H, Willett, W, Winqvist, R, Wolk, A, Wu, AH, Xia, L, Yamaji, T, Yang, XR, Har Yip, C, Yoo, K-Y, Yu, J-C, Zheng, W, Zheng, Y, Zhu, B, Ziogas, A, Ziv, E, ABCTB Investigators, ConFab/AOCS Investigators, Lakhani, Antoniou, AC, Droit, A, Andrulis, IL, Amos, CI, Couch, FJ, Pharoah, PDP, Chang-Claude, J, Hall, P, Hunter, DJ, Milne, RL, García-Closas, M, Schmidt, MK, Chanock, SJ, Dunning, AM, Edwards, SL, Bader, GD, Chenevix-Trench, G, Simard, J, Kraft, P, and Easton, DF

Subjects
ConFab/AOCS Investigators, ABCTB Investigators, skin and connective tissue diseases, 3. Good health, NBCS Collaborators
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

243. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility 'hot-spot'

Author

Johnatty, S. E., Beesley, J., Chen, X., Macgregor, S., Duffy, D. L., Spurdle, A. B., Defazio, A., Gava, N., Penelope Webb, Rossing, M. A., Doherty, J. A., Goodman, M. T., Lurie, G., Thompson, P. J., Wilkens, L. R., Ness, R. B., Moysich, K. B., Chang-Claude, J., Wang-Gohrke, S., Cramer, D. W., Terry, K. L., Hankinson, S. E., Tworoger, S. S., Garcia-Closas, M., Yang, H., Lissowska, J., Chanock, S. J., Pharoah, P. D., Song, H., Whitemore, A. S., Pearce, C. L., Stram, D. O., Wu, A. H., Pike, M. C., Gayther, S. A., Ramus, S. J., Menon, U., Gentry-Maharaj, A., Anton-Culver, H., Ziogas, A., Hogdall, E., Kjaer, S. K., Hogdall, C., Berchuck, A., Schildkraut, J. M., Iversen, E. S., Moorman, P. G., Phelan, C. M., Sellers, T. A., Cunningham, J. M., Vierkant, R. A., Rider, D. N., Goode, E. L., Haviv, I., Chenevix-Trench, G., Ovarian Cancer Association Consortium, Australian Ovarian Cancer Study Group, and Australian Cancer Study (Ovarian Cancer)

Subjects
Cancer Research, Genotype, lcsh:QH426-470, Colorectal cancer, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Telomerase reverse transcriptase, Genetics and Genomics/Cancer Genetics, Telomerase, Molecular Biology, Genetics and Genomics/Genetics of Disease, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Epithelial Cells, medicine.disease, 3. Good health, lcsh:Genetics, Serous fluid, Case-Control Studies, 030220 oncology & carcinogenesis, Cancer research, Chromosomes, Human, Pair 5, Female, Public Health and Epidemiology/Epidemiology, Stromal Cells, Ovarian cancer, Research Article
Abstract

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P per-allele, Author Summary In this article, we report the findings from a large-scale analysis of common variation in genes that are expressed as a consequence of interactions between ovarian cancer cells and their host micro-environment that could influence serous ovarian cancer risk. We evaluated 1,302 common variants within or near 173 genes in two large case-control studies from the Ovarian Cancer Association Consortium (OCAC) and selected three variants for further evaluation in sixteen OCAC studies and an additional 18 for evaluation in five OCAC studies. We observed a significantly increased risk of serous ovarian cancer associated with a variant in the telomerase reverse transcriptase (TERT) gene. Although TERT variants have not been previously shown to contribute to ovarian cancer risk, several studies have recently reported associations between TERT variants and other forms of cancer, including gliomas, lung cancer, adenocarcinoma, basal cell carcinoma, prostate cancer, and multiple other cancers. TERT encodes a protein that is essential for the replication and maintenance of chromosomal integrity during cell division. In cancer cells, TERT has been linked to genomic instability and tumour cell proliferation. Further studies are necessary to confirm our findings and to investigate the mechanisms for the observed association.

244. Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival

Author

Azzato, E. M., Tyrer, J., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Schulz-Wendtland, R., Stig Bojesen, Børge Nordestgaard, Flyger, H., Milne, R. L., Arias, J. I., Menendez, P., Benitez, J., Chang-Claude, J., Hein, R., Wang-Gohrke, S., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Margolin, S., Mannermaa, A., Kosma, V. M., Kataja, V., Beesley, J., Chen, X. Q., Chenevix-Trench, G., Couch, F. J., Olson, J. E., Fredericksen, Z. S., Wang, X. S., Giles Gaubert, Severi, G., Baglietto, L., Southey, M. C., Devilee, P., Tollenaar, R. A. E. M., Seynaeve, C., Garcia-Closas, M., Lissowska, J., Sherman, M. E., Bolton, K. L., Katrine Blædel Pinholt Hall, Czene, K., Cox, A., Brock, I. W., George Arthur Elliott, Greenberg, D., Anton-Culver, H., Ziogas, A., Humphreys, M., Easton, D. F., Caporaso, N. E., and Pharoah, P. D. P.

245. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Author

Cook, M., Lalloo, F., Stoppa-Lyonnet, D., Lindor, N., Casella, C., Andrulis, I. L., Peterlongo, P., Kaufman, B., Meindl, A., Sinilnikova, O. M., Cruger, D. G., Pfeiler, G., Evans, D. G., Van Den Ouweland, A., Piedmonte, M., Engel, C., Wijnen, J. T., Greene, M. H., Gershoni-Baruch, R., Viel, A., Montagna, M., Cook, J., Benítez, J., Claes, K., Hamann, U., Froster, U. G., Varon-Mateeva, R., Rennert, G., Moncoutier, V., Brunet, J., Eeles, R., Toland, A. E., Fricker, J. P., Versmold, B., Pichert, G., Basil, J., Rodriguez, G. C., Spiess, A. C., Yassin, Y., Oliver, C. T., Arver, B., Pita, G., Barile, M., Muller, D., Deiler, H., Spurdle, A. B., Miron, A., Schwartz, P. E., Beesley, J., Laitman, Y., Malmer, B., Olivier-Faivre, L., Lynch, H. T., Askmalm, M. S., Ditsch, N., Schaefer, D., Hansen, Thomas V.O., Hogervorst, F. B.L., Osorio, A., Garcíla, E. B.Gómez, Imyanitov, E. N., McGuffog, L., Wakeley, K., Couch, F. J., Douglas, F., Arnold, N., Ozcelik, H., Johannsson, O. T., Luccarini, C., Boggess, J. F., Jernström, H., Nathanson, K. L., Niederacher, D., Offit, K., Nevanlinna, H., Hopper, J. L., Milne, R. L., Domchek, S. M., Verhoef, S., Weerasooriya, N., Giraud, S., Zikan, M., Fiebig, B., Cassini, C., Gerdes, A. M., Kirchhoff, T., Ramón Y Cajal, T., Chen, X., Easton, D. F., Allavena, A., Peock, S., Goldgar, D., Dagan, E., Godwin, A. K., Caldes, T., Terry, M. B., Peyrat, J. P., Kosarin, K., Barjhoux, L., Barnett-Griness, O., Ding, Y. C., Friedman, E., Thomassen, M., Hodgson, S., Wang, X., Heikkinen, T., Manoukian, S., Morrison, P. J., Daly, M., Tizzoni, L., Yannoukakos, D., Antoniou, A. C., Caligo, M. A., Mai, P., Schmutzler, R. K., Blank, S. V., John, E. M., Healey, S., Foretova, L., Szabo, C. I., Radice, P., Chenevix-Trench, G., Cohen, S., Gschwantler-Kaulich, D., Frost, D., Révillion, F., Singer, C. F., Simard, J., Buys, S., Neuhausen, S. L., De La Hoya, M., Lejbkowicz, F., and Kontorovich, T.

Subjects
endocrine system diseases, skin and connective tissue diseases, 3. Good health
Abstract

Background:In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.Methods:We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.Results:We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers.Conclusion:This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

246. The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Amos, CI, Dennis, J, Wang, Z, Byun, J, Schumacher, FR, Gayther, SA, Casey, G, Hunter, DJ, Sellers, TA, Gruber, SB, Dunning, AM, Michailidou, K, Fachal, L, Doheny, K, Spurdle, AB, Li, Y, Xiao, X, Romm, J, Pugh, E, Coetzee, GA, Hazelett, DJ, Bojesen, SE, Caga-Anan, C, Haiman, CA, Kamal, A, Luccarini, C, Tessier, D, Vincent, D, Bacot, F, Van Den Berg, DJ, Nelson, S, Demetriades, S, Goldgar, DE, Couch, FJ, Forman, JL, Giles, GG, Conti, DV, Bickeböller, H, Risch, A, Waldenberger, M, Brüske-Hohlfeld, I, Hicks, BD, Ling, H, McGuffog, L, Lee, A, Kuchenbaecker, K, Soucy, P, Manz, J, Cunningham, JM, Butterbach, K, Kote-Jarai, Z, Kraft, P, FitzGerald, L, Lindström, S, Adams, M, McKay, JD, Phelan, CM, Benlloch, S, Kelemen, LE, Brennan, P, Riggan, M, O'Mara, TA, Shen, H, Shi, Y, Thompson, DJ, Goodman, MT, Nielsen, SF, Berchuck, A, Laboissiere, S, Schmit, SL, Shelford, T, Edlund, CK, Taylor, JA, Field, JK, Park, SK, Offit, K, Thomassen, M, Schmutzler, R, Ottini, L, Hung, RJ, Marchini, J, Amin Al Olama, A, Peters, U, Eeles, RA, Seldin, MF, Gillanders, E, Seminara, D, Antoniou, AC, Pharoah, PDP, Chenevix-Trench, G, Chanock, SJ, Simard, J, and Easton, DF

Subjects
Male, Genotype, Genetic Variation, Prognosis, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Neoplasms, Prevalence, Humans, Female, Genetic Predisposition to Disease, Selection, Genetic, Genome-Wide Association Study
Abstract

BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.

Catalog

Books, media, physical & digital resources
See catalog results